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FLASH GENE
Symbol TLR9 contributors: mct - updated : 28-06-2016
HGNC name toll-like receptor 9
HGNC id 15633
Location 3p21.1      Physical location : 52.255.097 - 52.260.179
Synonym name
  • Drosophila transmembrane receptor Toll homolog 9
  • CD289 antigen
  • Synonym symbol(s) CD289, UNQ5798/PRO19605
    DNA
    TYPE functioning gene
    STRUCTURE 5.08 kb     2 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    SRISNF2L 3p21.31 KIAA0809 protein ZSIG11 3p21.31 putative secreted protein ZSIG11 GRM2 3p21.3-p21.2 glutamate receptor, metabotropic 2 LOC389121 3 LOC389121 LOC389122 3 hypothetical gene supported by BC021188 LOC389123 3 similar to hypothetical protein MGC39725 LOC389124 3 similar to hypothetical protein MGC39725 MGC39725 3p21.31 hypothetical protein MGC39725 RNU3IP2 3p21.31 RNA, U3 small nucleolar interacting protein 2 ADPRTL3 3p22.2-p21.1 ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase)-like 3 GPR62 3p21.1 G protein-coupled receptor 62 PCBP4 3p21 poly(rC) binding protein 4 MGC15429 3p21.31 hypothetical protein MGC15429 DKFZP564O243 3p21.1 DKFZP564O243 protein ACY1 3p21.1 aminoacylase 1 RPL29 3q29 ribosomal protein L29 DUSP7 3p21.1 dual specificity phosphatase 7 DKFZP434C245 3p21.31 DKFZP434C245 protein LOC391538 3 similar to fructose-1,6-bisphosphate aldolase A ALAS1 3p21.1 aminolevulinate, delta-, synthase 1 TLR9 3p21.3 toll-like receptor 9 PTK9L 3p21.1 PTK9L protein tyrosine kinase 9-like (A6-related protein) FLJ32332 3p21.31 likely ortholog of mouse protein phosphatase 2C eta PRO2730 3p21.31 hypothetical protein PRO2730 GLYCTK 3p21.31 CG9886-like PPP2R5CP 3p21.3 protein phosphatase 2, regulatory subunit B (B56), gamma isoform pseudogene BAP1 3p21.31-p21.2 BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) PHF7 3p21.31 PHD finger protein 7 LOC56920 3p21.31 semaphorin sem2 TNNC1 3p21.3-p14.3 troponin C, slow NISCH 3p21.1 nischarin STAB1 3p21.31 stabilin 1 FLJ12442 3p21.31 hypothetical protein FLJ12442 PB1 3p21 hypothetical protein FLJ12442 NS 3p21.31 nucleostemin AD-017 3p21.31 glycosyltransferase AD-017 SPC12 3p21.31 signal peptidase 12kDa NEK4 3p21.1 NIMA (never in mitosis gene a)-related kinase 4 ITIH1 3p21.2-p21.1 inter-alpha (globulin) inhibitor, H1 polypeptide ITIH3 3p21.2-p21.1 pre-alpha (globulin) inhibitor, H3 polypeptide ITIH4 3p21.2-p21.1 inter-alpha (globulin) inhibitor H4 (plasma Kallikrein-sensitive glycoprotein) LOC389125 3 similar to hypothetical protein MGC52022 3p21.31 Similar to RIKEN cDNA 1810038N08 gene SFMBT1 3p21.31 Scm-like with four mbt domains 1
    regionally located close to PRPS2, linked to MYD88
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    2 - 3868 115.9 1032 - 2000 11130078
    biexonic
    - - 3110 109.4 975 - 2000 11022119
    monoexonic
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymph node    
     spleen     Homo sapiens
    Reproductivefemale systemoviduct   
     female systemuterus   
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Connectivebone   
    Epithelialbarrier liningendometrium  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticplatelet Homo sapiens
    Lymphoid/ImmuneB cell Homo sapiens
    Lymphoid/Immunedendritic cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • essential role for the N-terminal fragment of TLR9 in DNA sensing
  • an extracellular part composed of 18 leucine-rich repeats (LRR) that is necessary for ligand recognition
  • a cysteine rich region
  • a transmembrane segment
  • a cytoplasmic domain, the TOLL homology domain (TH), common to Toll and IL1 receptors (also called TIR domain)
  • three AAs in the C-terminus of the extracellular domain of TLR9 are required for ligand activation
  • both the C- and N-termini of the extracellular domain (ECD) are necessary for the function of TLR9
  • HOMOLOGY
    interspecies homolog to Drosophila transmembrane receptor Toll,9
    Homologene
    FAMILY
  • Toll-like receptor family
  • CATEGORY immunity/defense , receptor membrane
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    text
  • although ligand recognition occurs in endolysosomes, it has been reported that most, if not all, TLR9 resides in the endoplasmic reticulum (ER) of resting cells
  • sequestered in the endoplasmic reticulum (ER) in a resting state and traffic to endolysosomes upon ligand-induced stimulation
  • translocates from ER to endolysosomes through the Golgi complex and that Golgi export is required for optimal TLR9 signaling
  • primarily resides in the endoplasmic reticulum, traffics to endosomes, is proteolytically processed and responds to DNA
  • expressed on the surface of splenic dendritic cells
  • localized in the endolysosome
  • basic FUNCTION
  • pathogen recognition and activation of innate immunity
  • potential inducer of apoptosis and septic shock
  • activating NF-Kappa B signaling pathway
  • can recognize nucleic acids and trigger signaling cascades that activate plasmacytoid dendritic cells to produce interferon-alpha (thus contributing to the pathogenesis of systemic lupus erythematosus)
  • mediating cellular response to unmethylated CpG dinucleotides in bacterial DNA to mount an innate immune response
  • required for effective innate immune responses against Gram-negative bacterial pathogens
  • blocks osteoclast differentiation through induction of phosphatase
  • initiate immune responses to infection by recognizing microbial nucleic acid
  • requirement for processing of TLR9 may represent an evolutionary strategy to ensure proper self/non-self discrimination based on nucleic acid recognition
  • recognize pathogen-derived nucleotides in intracellular compartments and respond to host-derived nucleotides as well, and they have been implicated in a variety of autoimmune diseases
  • TLR9-induced suppression of EBV lytic gene expression is dependent on the TLR9–MyD88 signaling axis
  • TLR9–MyD88 activation leading to histone modification might be the signaling event responsible for the interaction between the malaria parasite P. falciparum and EBV gene expression in B cells contributing to the pathogenesis of endemic Burkitt lymphoma
  • with TLR7, are required for plasmacytoid dendritic cells
  • senses DNA with unmethylated CpG motifs derived from bacteria and viruses
  • TLR9 signaling pathway is involved in inflammatory responses in failing hearts in response to pressure overload and plays an important role in the pathogenesis of heart failure
  • mitochondrial DNA that escapes from autophagy-mediated degradation cell-autonomously leads to TLR9-mediated inflammatory responses in cardiomyocytes, myocarditis, and dilated cardiomyopathy
  • cell death and injury result in the release of mtDNA (mitochondrial DNA) that acts via TLR9 (Toll-like receptor 9), a pattern recognition receptor of the immune system which detects bacterial and viral DNA
  • platelet TLR9 is a functional platelet receptor that links oxidative stress, innate immunity, and thrombosis
  • TLR9-mediated recognition of viral and bacterial DNA activates the innate immune system
  • would potentially signal in acidic pH as endolysosome/lysosome condition
  • has paradoxical roles in regulating anti-DNA B cells
  • initiates inflammatory response by recognizing DNA, imported by infection or released from tissue damage
  • role of TLR9 in energy metabolism and cellular protection in cardiomyocytes and neurons
  • component of the innate immune system, which recognizes the DNA of both pathogens and hosts, and can drive autoimmune diseases
  • TLR7 plays a central role in early immune activation during malaria infection, whereas TLR7 and TLR9 contribute combinatorially to immune responses as infection progresses
  • distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, as well as TLR7 to promote, the clinical features of systemic erythematosus lupus
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS immunity/defense
    text apoptosis of infected cells
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • component in the recognition of immunostimulating bacterial CpG-DNA motifs, in different subsets of human peripheral blood mononuclear cells (PBMC)
  • TLR9–MyD88 signaling axis is implicated in TLR9-induced suppression of EBV lytic gene expression
  • forms a complex with AP3B1 and promotes association of TRAF3 and IRF7
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, UNC93B1
  • HSP90B1 is critical for both TLR9 egress from the ER, and for protein conformational stability in the endosomal compartment
  • IRF5 is a transcription factor activated by toll like receptor TLR7 and TLR9 during innate immune responses
  • DOCK8 functions as an adaptor in a TLR9-MYD88 signaling pathway in B cells
  • is essential for dendritic cells (DC) activation caused by CpG oligonucleotides (ODN)
  • physical association of TLR9, ICAM1 and TRAF6 leads to activation of noncanonical NFKB1 signalling
  • signaling cascades driven by the BCR and TLR9 have a newly identified meeting point at TBX21(
  • BTK is an important player for TLR9 but not TLR7 signaling in human Plasmacytoid dendritic cells (PDCs)
  • BTK regulates dendritic cell responses upon TLR9 engagement in terms of activation, cytokine production, and STAT1/3 upregulation
  • to restrict Nucleic acid (NA)-sensing in endolysosomes, TLR7/9 trafficking is tightly controlled by a multiple transmembrane protein UNC93B1
  • TRIM35 is a negative feedback regulator of TLR7/9-mediated type I IFN production due to its ability to suppress the stability of IRF7
  • SARM1, mediates TLR7/TLR9-induced apoptosis in neurons
  • TRAF6-mediated degradation of DOK3 is required for production of IL6 and TNF in TLR9 signaling
  • IRF8 inhibits TLR9-dependent gene expression by directly blocking the activity of IRF5
  • CAMP selectively modulated synthesis of TLR4 and TLR9 in intestinal epithelium, but only when cells were exposed to virulence factors, mostly from apical surfaces (pMID: 28988039)
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in primary Sjogren syndrome
    constitutional       gain of function
    results in inhibition of TNFSF11-induced osteoclastogenesis
    tumoral     --other  
    aberrantly expressed in neuroblastoma (NB) cells
    tumoral     --over  
    associated with poor differentiation, a high proliferation rate and disseminated in oesophageal adenocarcinoma
    Susceptibility
  • to asthma
  • to systemic lupus erythematosus (SLE)
  • Variant & Polymorphism SNP
  • 1237 C increases risk for asthma in Europeans
  • TLR9 C > T (rs352140) polymorphism might contribute to renal and immunologic disorders in SLE patients and to the presence of anti-dsDNA Ab
  • Candidate gene
    Marker
  • circulating mtDNA may be potential markers of early detection of pre-eclampsia
  • Therapy target
    SystemTypeDisorderPubmed
    cancerbrainglioma/neuroblstoma
    may represent a novel theranostic target in this disease
    reproductionpregnancy 
    anti-TLR9 treatments may be promising in the management of the pre-eclampsia
    ANIMAL & CELL MODELS